The present application is related to pharmaceutically acceptable salts of alkaloids or amine containing compounds, particularly those exhibiting stimulant, appetite suppressant, decongestion, physiological and/or psychological activity in humans. The invention embodies a platform technology for incorporating a targeted release mechanism within an organic-acid addition salt of amine-containing pharmaceutically active compounds. More specifically, many final dose drug products are formulated with active pharmaceutical ingredients (drug substances) that provide pain relief, mood alteration or modification, sense of euphoria, analgesia, sedation, or in addition, affect a psychotropic response. These drug products most often have the highest probability of abuse. As discussed herein, abuse means human use of physiologically or psychologically active compounds for purposes than otherwise intended or legally prescribed. As an example, the drug product Oxycontin® contains the drug substance oxycodone hydrochloride. The U.S. Drug Enforcement Agency (DEA) recognizes Oxycontin® as being implicated in a huge number of drug abuse cases resulting in a substantial societal impact. Beyond the human suffering emanating from drug abuse, the financial costs to society are a well-known burden shared by all citizens. The method of abuse, once the drug product is obtained (usually by illegal means), is to remove any coating on the tablet (often by lemon juice or saliva) followed by grinding the remaining portion into a powder. The powder is then inhaled into the nasal passageway (i.e. sniffed or “snorted”) to impart the “high” to the abuser. Alternatively, the powder can be extracted or melted and the drug abuse performed by intravenous injection. Additional routes of administration for abusive purposes include the muscosal surfaces (ocular, nasal, pulmonary, buccal, sublingual, gingival, rectal and vaginal mucosa).
Of significant seriousness with detrimental consequences to society is the illicit production of methamphetamine (“meth”). Frequently, laboratories illegally producing meth are ill-equipped for the required synthetic transformations and as a consequence, introduce significant health risks to the laboratory operators. Serious conflagrations and fires have resulted from poorly operated laboratories and these incidents resulted in burn victims which in turn are overwhelming the resources of citizen-funded burn centers. Further, law enforcement is often exposed to hazardous chemical situations and local environmental damage occurs because of the lack of containment of toxic and/or hazardous chemicals. Key raw materials used to produce “meth” include ephedrine and pseudoephedrine which are most often found as the active ingredient in legitimate, useful cough and cold, and allergy medicines. Pseudoephedrine or ephedrine is easily extracted from these medicines by preferentially dissolving the active ingredient pseudoephedrine hydrochloride or ephedrine hydrochloride into, for example, isopropyl (“rubbing”) alcohol followed by isolation and recovery by evaporation of the solvent. These beneficial products are now receiving more scrutiny and market restriction because of their illicit use to manufacture methamphetamine, “meth”.
In a report dated July 2005 from the National Center on Addiction and Substance Abuse (CASA) at Columbia University and entitled “Under the Counter: The Diversion and Abuse of Controlled Prescription Drugs in the US”, a recommendation was extolled for the FDA to require controlled drug manufacturers to take measures, where possible, to minimize the abuse potential of the drugs they manufacture. The suggested route for accomplishing this task was to formulate or reformulate the drug products to retain the desired therapeutic effect while preventing abuse. Also contained within the report are the disturbing data representing severe societal repercussions that in the period 1992 to 2003, drug abuse cases increased seven times faster than the increase in the US population.
Prior to the CASA report, the pharmaceutical industry recognized the severity of the drug abuse problem and innovative techniques to mitigate or control non-medical uses of drug substances and products have been published. Essentially, three mechanisms have been reported which minimize the potential for drug abuse: 1) encase within the drug product's formulation an antagonist to the drug substance, 2) chemically modify the drug substance to yield a prodrug, and 3) employ formulation techniques to yield products resistant to drug abuse.
The combination product wherein the drug substance prone to abuse is simultaneously delivered with an antagonist which is activated only under special circumstances typically employed by abusers (crushing, chewing, or dissolving) has received significant attention. Successful clinical trials were announced by the company Alpharma and reported in FDAnews Drug Pipeline Alert™ (Volume 4, No. 193, Oct. 3, 2006). The capsule formulation consists of an extended-release opioid with a sequestered core of naltrexone, an opioid antagonist. The sequestering subunit enabling this technology is described by Boehm in United States Patent Application Publication US 2004/01341552 A1, and is totally incorporated herein by reference.
Similarly, Elite Pharmaceuticals is reportedly initiating a Phase II clinical trial of its abuse resistant pain drug also employing the antagonist naltrexone hydrochloride. The report found in FDAnews Drug Pipeline Alert™ (Volume 4, No. 179, Sep. 13, 2006) states the previous Phase 1 trial confirmed the technical approach such that when the drug product was taken as intended, no antagonist was measured in the blood stream. However, if the drug product was crushed, the antagonist was released into the blood stream and the euphoria normally experience by oxycodone hydrochloride abusers was reduced.
Alternatives to the preceding agonist/antagonist approach include the preparation of prodrugs that exhibit their therapeutic value only when used for their intended purpose. Buchwald, et al. in United States Patent Application Publication (US 2004/0058946 A1), the disclosure of which is totally incorporated herein by reference, identifies modified oxycodone derivatives (prodrug) such that its physiological activity is only observed after the prodrug is converted to the drug in the mammalian gastrointestinal tract. Mickle, et al. in United States Patent Application Publication (US 2005/0266070 A1), the disclosure of which is totally incorporated herein by reference, identifies hydrocodone conjugates that release the drug substance following oral administration yet are resistant to intravenous or intranasal abuse.
Similarly, U.S. Pat. No. 7,105,486 B2 (Mickle et al.) the disclosure of which is totally incorporated herein by reference, describes the covalent attachment of L-lysine to the drug substance, amphetamine, to provide compounds and compositions exhibiting abuse-resistant properties and useful for the treatment of disorders including attention deficit hyperactivity disorder (ADHD), attention deficit disorder (ADD), narcolepsy and obesity.
In regard to formulation techniques, Vaghefi, et al. in United States Patent Application Publication (US 2006/0104909 A1), the disclosure of which is totally incorporated herein by reference, describes the creation of a matrix of discrete particles within which an active ingredient susceptible to abuse is distributed. The particles are coated with a water insoluble coating material creating the matrix from which the active ingredient is difficult to separate. The methodology provides a controlled release pharmaceutical composition having a reduced potential for abuse.
Another formulation technique is described in Unites States Patent Application Publication US 2006/0051298 A1, (Groenewoud), the disclosure of which is totally incorporated herein by reference. The abuse resistant pharmaceutical dosage consists of an active ingredient and at least one gel forming granule, and the granule possesses an outer brittle coating. Should the outer coating be crushed (for the purpose of abusing the drug), the subsequent exposure to an aqueous media creates a gel and inhibits extraction of the active ingredient.
Yet another formulation technique, but from the perspective of utilizing an agonist, is described in U.S. Pat. No. 4,622,244 (Lapka et al.), the disclosure of which is totally incorporated herein by reference. In Lapka et al. the inventors recommend the exposure of the drug substance, naltrexone pamoate, and a bioabsorbable polymer material to humidity before a microencapsulation process occurs. The equilibration in a humid environment of a hydrophobic drug and other materials impacts important effects on the nature of the microcapsule thus formed.
Similarly, in U.S. Pat. No. 6,203,813 B1 (Gooberman), the disclosure of which is totally incorporated herein by reference, the authors make reference to the controlled release of an opiate antagonist implant of naltrexone pamoate in a linear poly(ortho) ester.
The three mechanistic approaches presented above (antagonist, prodrug and formulation) attempt to address abuse potential by impacting the route of administration, or to differentiate the physiological environment in which the drug fulfills its intended purpose versus the drug's misuse. The release of the antagonist by illicit mechanical or physical manipulations effectively “neutralizes” the attempted abuse by the perpetrator. Alternatively, addiction could be treated by the implant of a slow-release of an antagonist as in Gooberman. A fundamental disadvantage to this combination drug/anti-drug technology is the presence of two drug substances in a product formulation for which an equivalent pharmacokinetic profile must fit potential users (or abusers) of the drug. There is also the added cost of the additional antagonist. As a technology, the antagonist approach does not offer a platform methodology to the many controlled substances having medicinal benefit. While the opioids as a class may have readily available antagonists (e.g naltrexone and naloxone), other controlled substances may not have effective antagonists. From a marketing and patient perspective, many perceived problems may arise particularly if the reliability or the intended effect of the drug is questioned.
In regard to the prodrug approach (for which not all abused drugs are susceptible to this approach), elegant chemistry is employed as an anti-abuse technology. In this case, release of the drug substance is controlled by physiological, enzymatic cleavage of the covalently bound protecting group attached to the drug substance. Theoretically, the drug is only released when the prodrug is in the intended environment for its absorption. Unfortunately, drug abusers and those illicitly supplying drugs for abuse understand free-basing techniques which are directly applicable to liberating a drug from its prodrug analog. Further the physiological aspects of the prodrug may alter the drug's anticipated pharmacokinetic profile and sufficient concentrations may not be available in certain patient populations to achieve the legitimate therapeutic effect.
The third mechanism employed for providing abuse-resistant drug products is through formulation techniques. Sophisticated manufacturing techniques are employed to produce products whose anti-abuse mechanism relies on forming a matrix from which the drug substance cannot easily be extracted. As with all formulated products, content uniformity becomes a dominating factor at the commercial scale. In the formulation process during commercial scale product manufacture, the assurance that each individual dose is identical is of critical importance. The matrix technology has inherent limitations for achieving content uniformity from a chemical assay perspective. In addition, the anti-abuse property must be maintained for every single dosage presentation and performance (anti-abuse) uniformity is likely challenged. Here too, encasing the drug in a matrix inherently alters the drug's pharmacokinetic profile and sufficient concentration may not be obtainable to achieve the desired therapeutic effect.
Historically, the preparation of mineral acid salts of basic drugs has been the preferred choice for imparting immediate release characteristics to drug substances. A drug substance's dissolution profile can influence its absorption characteristics, and in the case of a drug with a potential for abuse by snorting into the nasal cavity, rapid dissolution in nasal fluid would be required. Other factors influencing the absorption of the drug include the physiological pH encountered, the drug substance's morphology, the particle size and the particle size distribution. Typically, the nasal cavity pH is about 4.5 which provides for the rapid dissolution and absorption of highly soluble, mineral acid salts of drug substances.
U.S. Pat. No. 5,232,919 (Scheffler, et al.), the disclosure of which is totally incorporated herein by reference, discloses azelastine embonate and pharmaceutical formulations/compositions which contain it; the embonate salt to eliminate the bitter taste of azelastine alone. The term embonate is a synonym for pamoate.
French Patent 1,461,407 (Saias, et al.), the disclosure of which is totally incorporated herein by reference, discloses a process for the preparation of amine pamoates where the amine component includes piperazine, promethazine, papaverine, pholocodine, codeine, noracotine and chlorpheniramine.
The United Kingdom Patent Specification No. 295,656, the disclosure of which is totally incorporated herein by reference, discloses a process for the manufacture of difficulty soluble salts of organic bases and alkaloids. The disclosure further indicates the process for manufacture provides sparingly soluble and tasteless salts of organic nitrogenous basic compounds including alkaloids.
U.S. Pat. No. 3,502,661 (Kasubick, et al.), the disclosure of which is totally incorporated herein by reference, discloses a process for the preparation of variously substituted pyridinium and imidazolines along with their acid addition salts. Some examples indicate pamoate salts were prepared for select organic bases.
U.S. Pat. No. 2,925,417 (Elslager, et al.), the disclosure of which is totally incorporated herein by reference, discloses quinolinium salts of pamoic acid and a process for their manufacture.
U.S. Pat. No. 5,776,885 (Orsolini, et al.), the disclosure of which is totally incorporated herein by reference, discloses a pharmaceutical composition for the sustained and controlled release of water insoluble polypeptides whereby the therapeutically active peptide is in the form of its pamoate, tannate or stearate salt.
U.S. Pat. No. 5,445,832 (Orsolini, et al.), the disclosure of which is totally incorporated herein by reference, discloses a process for the preparation of microspheres made of a biodegradable polymeric material whereby a water soluble peptide or peptide salt is converted into a corresponding water-insoluble peptide salt selected from pamoates, stearates or palmitates of the peptide.
U.S. Pat. No. 5,439,688 (Orsolini, et al.), the disclosure of which is totally incorporated herein by reference, discloses a process for preparing a pharmaceutical composition in the form of microparticles designed for the controlled release of a drug that includes a biodegradable polymer and where the active ingredient can be selected from a group of possible salts, one being a pamoate.
U.S. Pat. No. 5,271,946 (Hettche) the disclosure of which is totally incorporated herein by reference, discloses a controlled release azelastine containing pharmaceutical composition whereby azelastine is incorporated into the formulation as its pamoate or other pharmaceutically active salt.
U.S. Pat. No. 5,225,205 (Orsolini, et al.), the disclosure of which is totally incorporated herein by reference, discloses a pharmaceutical composition in the form of microparticles; the formulation consisting of a peptide as its pamoate, tannate, stearate or palmitate salt; the formulation to provide a controlled release, pharmaceutical composition for the prolonged release of a medicamentous substance.
The illicit manufacture and consumption of methamphetamine has reached epidemic proportion in the Nation. This aspect of drug abuse has contributed to a number of society's ills beyond the detrimental effects to those people abusing the drug. Increased levels of crime are perpetrated to support the raw material supply and subsequent conversion of over-the-counter or easily obtained legitimate drug products to methamphetamine. Often, the chemical conversion, for instance, of pseudoephedrine to methamphetamine, is performed by those inexperienced or ignorant of the severe danger and potential for substantial physical harm and property damage. The news media regularly reports of dwellings used for illicit methamphetamine production catching on fire or are so severely contaminated with chemicals so as to prevent inhabitation. Often the conflagration of fire and chemical exposure injures the illicit processors to the extent they require substantial medical treatment (particularly in expensive burn centers); on other occasions, injury leads directly to death. The demand on a community's limited resources can be overwhelming—to law enforcement, fire departments, medical services and social services.
Administrative actions to suppress illicit methamphetamine production have also had negative consequences. Removing pseudoephedrine from immediate consumer access deprives legitimate use of a needed medicine to the general population. Further, the restrictions on pseudoephedrine availability may suppress some small scale “local” production, but have the effect of creating an industry for organized criminal activity. Arguably, the restriction on legitimate drug product created additional negative consequences for the consumer and the taxpayer: to the consumer, pricing has escalated on the restricted products, and to the taxpayer, the problem has been escalated to an international concern.
Drug products formulated with pseudoephedrine or ephedrine represent products serving legitimate medical needs, and as such, should be readily available to the discerning consumer without impedance—however well-intended the bureaucratic imposition to move these products to “behind-the-counter” availability. The invention described herein provides a chemical means to interrupt the reduction of pseudoephedrine, ephedrine or similar precursors and thereby prevent or restrict the formation of methamphetamine.
In spite of the long history of research directed at prohibiting the illicit use of pharmaceutical compounds the problem remains. There has yet to be a suitable solution which is widely applicable, easily implemented and applicable to a wide range of active pharmaceutical ingredients. The present invention provides a platform technology to address this long standing problem.